2-(3-Pyridyl)-5-thiazolecarboxamides

ABSTRACT

Certain 2-(3-pyridyl) thiazoles are useful for the control of insects, and are particularly effective against aphids. Many of these thiazoles are new compounds.

This is a continuation, of application Ser. No. 861,768, filed Dec. 19,1977 now abandoned which is a continuation-in-part of application Ser.No. 140,571 filed May 5, 1971 now abandoned and relates to the use ofcertain 2-(3-pyridyl) thiazoles for use in selectively controllinginsects, and, particularly, aphids. Many of these thiazoles are newcompounds.

Some 2-(3-pyridyl) thiazoles are known from the prior art. See, forexample, the following references:

Karrer and Schukri, Helv. Chim. Acta 28, 820 (1945);

Chemical Abstracts (CA) 54, 4571c (1960); C. A. 54, 9891c (1960); C. A.55, 24739e (1961); C. A. 57, 16586b; C. A. 57, 9813b (1962); C. A. 49,8249C (1955); C. A. 62, 10440g (1965); C. A. 62, 7764c (1965); C. A. 65,8919b (1966); C. A. 48, 1341a (1954); C. A. 59, 11936b (1963); C. A. 63,3496a (1965); and C. A. 59, 635de (1963).

However, none of these articles discloses such thiazoles as being usefulin controlling insects.

In accordance with this invention, insects are effectively controlledusing 2-(3-pyridyl) thiazoles or acid salts thereof, of the generalformula (I): ##STR1## wherein: R², R³, R⁴ and R⁵ can be the same ordifferent and can be hydrogen or an alkyl group containing up to 3carbon atoms, and R and R¹ can be the same or different and are:

(a) hydrogen

(b) an alkyl group containing up to 6 carbon atoms

(c) a cycloalkyl group containing 5 to 8 carbon atoms

(d) a cyano group

(e) a nitro group

(f) --R¹⁰ COXR⁶ wherein R¹⁰ is a single covalent bond or a divalentaliphatic acyclic hydrocarbyl group containing 1 to 3 carbon atoms, X isdivalent sulfur or oxygen, and R⁶ can be

(i) hydrogen

(ii) a metal ion selected from the group, consisting of aluminum,cadmium, calcium, cobalt, copper, iron, lithium, magnesium, manganese,mercury, nickel, potassium, sodium and, zinc, or a primary or secondaryalkylammonium or alkanolammonium moiety

(iii) an alkyl, alkenyl or alkynyl group containing up to 12 carbonatoms

(iv) a cycloalkyl or cycloalkenyl group containing 5 to 8 carbon atoms

(v) an aryl, aralkyl, alkyl substituted aralkyl, or alkaryl groupcontaining 6 to 10 carbon atoms

(vi) an hydroxyalkyl, alkoxyalkyl, alkylaminoalkyl, or aralkylaminoalkylgroup containing up to 10 carbon atoms

(g) --R¹⁰ COR⁷ where R¹⁰ has the meaning specified in (f) and wherein R⁷can be:

(i) hydrogen

(ii) an alkyl group containing 1 to 3 carbon atoms or phenyl

(iii) an --NR⁸ R⁹ group wherein R⁸ and R⁹ can be the same or differentand can be hydrogen, alkyl, alkenyl, alkynyl, hydroxyalkyl, alkoxyalkyl,aminoalkyl, and alkylaminoalkyl containing up to 8 carbon atoms, acycloalkyl or cycloalkenyl of 5 to 8 carbon atoms, an aryl, haloaryl,aralkyl or alkaryl having 6 to 10 carbon atoms, or a nitrogen-containinghererocyclic aromatic radical having 5 to 10 carbon atoms, or R⁸ and R⁹are joined together to form an alkyl substituted or non-substituted ringstructure containing 4 to 7 carbon atoms and up to 2 atoms selected fromnitrogen and oxygen, or R⁸ or R⁹ forms an alkylene group of 2 to 4carbon atoms joining two members of the general formula, the membersbeing the same or different.

(h) R¹ and R are joined together to form a benzene ring fused to thethiazole ring; or, an acid salt or metal complex of said general formulacompound.

Acid salts and metal complexes of these thiazoles are also effective incontrolling insects, particularly the salts made by reaction withhydrogen chloride, hydrogen bromide, hydrogen iodide, and sulfuric acid.The metal complexes can be of the types described in the book entitledPyridine and its Derivatives, E. Klingsberg, editor, part I, pages 40ff., Interscience Publishers, New York, 1960.

Within the generic class, the preferred compounds of the general formula(I) are those where: R², R³, R⁴ and R⁵ can be hydrogen or methyl, R canbe:

(a) hydrogen

(b) methyl

(c) a cyano group

(d) a nitro group

(e) --R¹⁰ COXR⁶ wherein R¹⁰ is a single covalent bond or methylene, X isdivalent sulfur or oxygen, and R⁶ can be:

(i) hydrogen

(ii) a metal salt selected from the group consisting of sodium,potassium and zinc, or a primary or secondary alkylammonium oralkanolammonium moiety

(iii) an alkyl, alkenyl or alknyl group containing up to 5 carbon atoms

(iv) a cycloalkyl group having 5 to 6 carbon atoms

(v) phenyl

(vi) an hydroxyalkyl, alkoxyalkyl, or alkylaminoalkyl group containingup to 4 carbon atoms

(f) --R¹⁰ COR⁷ wherein R¹⁰ has the meaning specified in (e) and whereinR⁷ can be:

(i) hydrogen

(ii) methyl

(iii) --NR⁸ R⁹ wherein R⁸ and R⁹ can be the same or different and can behydrogen, an alkyl, alkenyl, alkynyl, hydroxyalkyl or alkoxyalkyl havingup to 4 carbon atoms, an aminoalkyl or alkylaminoalkyl having no morethan 5 carbon atoms wherein the sum of the carbon atoms of R⁸ and R⁹ isno greater than 6, a cycloalkyl having 5 to 6 carbon atoms, phenyl, orR⁸ and R⁹ are joined together to form an alkyl substituted ornon-substituted ring structure containing 4 to 6 carbon atoms and up to2 atoms selected from nitrogen and oxygen

R¹ can be:

(a) hydrogen

(b) an alkylyl having from 1 to 3 carbon atoms

(c) --R¹⁰ COXR⁶ wherein R¹⁰ is methylene, X is divalent sulfur oroxygen, and R⁶ can be hydrogen, an alkyl having 1 to 2 carbon atoms, orNH₂ ; or,

an acid salt or metal complex of said general formula compound.

The most preferred compounds of the general formula (I) are those where:R², R³, R⁴ and R⁵ are hydrogen, R can be hydrogen, methyl, ethyl, acyano group, a nitro group or --COXR⁶ wherein X, is divalent sulfur oroxygen and wherein R⁶ can be:

(a) an alkyl, alkenyl, alkynyl, hydroxyalkyl, alkoxyalkyl, oralkylaminoalkyl group having up to 4 carbon atoms or

(b) phenyl or cyclohexyl, or

R is --CONR⁸ R⁹ wherein R⁸ and R⁹ can be the same or different and canbe hydrogen or alkyl group having 1 to 3 carbon atoms, or when either R⁸or R⁹ is hydrogen, the other group can be an hydroxyalkyl having up to 2carbon atoms, an alkoxyalkyl having 1 to 4 carbon atoms, alkylaminoalkylhaving 1 to 5 carbon atoms or a cyclohexyl radical, or R⁸ and R⁹ can bejoined together to form a ring structure which can contain an oxygenatom,

and R¹ can be hydrogen, methyl, --CH₂ COOCH₃, --CH₂ COOC₂ H₅, or --CH₂CONH₂ ; or,

a salt complex formed by the association of said general formulacompound with an acid selected from the group HCl, HBr, HI and H₂ SO₄.

Compounds falling within the scope of general formula (I) and founduseful in controlling insects include:

2-(3-pyridyl)-4-ethyl-5-propylthiazole

5-propyl-2-(3-pyridyl)thiazole

4-propyl-2-(3-pyridyl)-5-thiazolecarbonitrile

5-nitro-4-propyl-2-(3-pyridyl)thiazole, the HCl salt thereof

2-(3-pyridyl)-4-thiazolecarbonitrile

N,N-dimethyl-2-(3-pyridyl)-4-thiazolepropionamide

N,N,4-trimethyl-2-(3-pyridyl)-5-thiazoleacetamide

N,N,N',N'-tetramethyl-2-(3-pyridyl)-4,5-thiazole dicarboxamide

Dichloro [N,N,4-trimethyl-2-(3-pyridyl)-5-thiazolecarboxamide]zinc

N-butyl-N,4-dimethyl-2-(3-pyridyl)-5-thiazole carboxamide

2-(5-methyl-3-pyridyl)benzothiazole

N,N-diethyl-5-nitro-2-(3-pyridyl)-4-thiazoleacetamide

It is of particular significance to note that the compounds of theinvention derive their useful activity from the -2-(3-pyridyl)thiazolemoiety whereas substituents R-R⁵ are important only to the extent ofcontrolling the degree of activity of the compounds.

The compounds of this invention are generally effective against insectsof the class Insecta and particularly insects in the orders Hemipteraand Homoptera. In these orders, members of the families Aphididae(aphids), Psyllidae (psyllas) and Aleyrodidae (white flies) arecontrolled most effectively.

Table A below lists some of the harmful insects which these compoundscontrol effectively.

                  TABLE A                                                         ______________________________________                                        Order Homoptera             Common Name                                       Common Name    Scientific Name                                                                            of Host Plant                                     ______________________________________                                        Family Aphididae                                                              Green apple aphid                                                                            Aphis pomi   Apple                                             Rosy apple aphid                                                                             Auraphis rosea                                                                             Apple                                             Apple grain aphid                                                                            Rhopalosiphium                                                                             Barley                                                           prunifoliae                                                    Corn leaf aphid                                                                              Rhopalosiphium                                                                             Barley                                                           maidis                                                         Green cabbage aphid                                                                          Brevicoryne  Collard                                                          brassica                                                       Cotton aphid   Aphis gossypii                                                                             Cotton                                            Green peach aphid                                                                            Myzus persicae                                                                             Cotton                                            Black bean aphid                                                                             Aphis fabae  Cow peas                                          Black pecan aphid                                                                            Timocallis   Pecan                                                            caryaefoliae                                                   Yellow aphid   Monellia spp.                                                                              Pecan                                             Pea aphid      Macrosiphum pisi                                                                           Broadbean                                         Family Psyllidae                                                              Pear Psylla    Psylla pyricola                                                                            Pear                                              Family Aleyrodidae                                                            Greenhouse white                                                                             Trialeurodes Tobacco                                           fly            vaporariorum                                                   ______________________________________                                    

Beneficial insects, such as hymenopterous wasps, which feed upon aphids,are apparently unaffected by these compounds at dosage rates effectivefor aphid control. Other beneficial insects which enjoy similaradvantages include lady bird beetles (Coccinellidae), syrphid fly larvae(Syrphidae) and lace wings (Chrysopidae), and parasitic insects ofsuperfamilies such as Ichneumonidea and Chalcidoidea.

For practical applications, the compounds of the invention can be usedalone, or dissolved or suspended in suitable carriers such as water,alcohols, ketones, phenols, toluene or xylenes. Optionally, one or moresurface active agent and/or inert diluent can be added to theformulation to facilitate handling. The formulations can take the formof dusts, granules, wettable powders, emulsifiable concentrates, watersolution concentrates, or a water soluble solid.

These formulations will contain amounts of the compounds effective forthe particular method of insect control. These amounts can vary widely;typically, the range is from 0.1 to 95% active ingredient. Spraydilutions can contain from a few parts per million to full strengthconcentrates applied by ultra low volume techniques. Concentration perunit area, where plants are the area treated, can vary from 0.1 to 10pounds per acre.

Commonly, the compounds are applied directly to the insects, or to areasthe insects occupy. To control aphids, for example, sprays of thecompounds are applied to the aphids directly, to plants upon which theyfeed, or both. Sprays applied to the aphid-infested plants killeffectively even if direct contact does not occur, as where the aphidscling to the inner surface of a curled up leaf or lie in a protectedleaf sheath of, for example, a grain plant. Another effective method ofattack involves application of the compounds to the soil or other mediumin which insect-infested plants live. The compounds act systemicallyupon the insects after the compound is absorbed by the plants.

Harmful insects attack a wide variety of plants, including bothornamental and agricultural plants such as chrysanthemum, azalea,cotton, corn, wheat, apple and tobacco, and inflict damage bywithdrawing vital juices from the plants, by secreting toxins, and oftenby transmitting diseases. These compounds can prevent such damage. Themethods of application, and the selection and concentration of thesecompounds, will be varied depending upon such circumstances as area,climate, prevalent diseases, etc. One skilled in the art can select theproper approach by simple experiments.

Many of the insecticidal compounds of this invention are new. The newcompounds have the general formula (I) and include those where R², R³,R⁴ and R⁵ can be the same or different and can be hydrogen or an alkylgroup containing up to 3 carbon atoms, and R and R¹ can be the same ordifferent and are:

(a) hydrogen, provided R¹ is not hydrogen, methyl, --COOH or --COOC₂ H₅

(b) methyl, provided R¹ is not hydrogen

(c) an alkyl group containing up to 6 carbon atoms

(d) a cycloalkyl group containing 5 to 8 carbon atoms

(e) a cyano group

(f) a nitro group

(g) --R¹⁰ COXR⁶ wherein R¹⁰ is a single covalent bond or a divalentaliphatic acyclic hydrocarbyl group containing 1 to 3 carbon atoms, X isdivalent sulfur or oxygen, and R⁶ can be

(i) hydrogen

(ii) a metal ion selected from the group consisting of aluminum,cadmium, calcium, cobalt, copper, iron, lithium, magnesium, manganese,mercury, nickel, potassium, sodium and zinc, or a primary or secondaryalkylammonium or alkanolammonium moiety

(iii) an alkyl, alkenyl or alkynyl group containing up to 12 carbonatoms

(iv) a cycloalkyl or cycloalkenyl group containing 5 to 8 carbon atoms

(v) an aryl, aralkyl, alkyl substituted aralkyl, or alkaryl groupcontaining 6 to 10 carbon atoms

(vi) an hydroxyalkyl, alkoxyalkyl, alkylaminoalkyl, or aralkylaminoalkylgroup containing up to 10 carbon atoms.

(h) --R¹⁰ COR⁷ where R¹⁰ has the meaning specified in (g) and wherein R⁷can be:

(i) hydrogen

(ii) an alkyl group containing 1 to 3 carbon atoms or phenyl

(iii) an --NR⁸ R⁹ group wherein R⁸ and R⁹ can be the same or differentand can be: hydrogen, alkyl, alkenyl, alkynyl, hydroxyalkyl,alkoxyalkyl, aminoalkyl and alkylaminoalkyl containing up to 8 carbonatoms, a cycloalkyl or cycloalkenyl of 5 to 8 carbon atoms, an aryl,haloaryl, aralkyl, alkaryl having 6 to 10 carbon atoms, ornitrogen-containing heterocyclic aromatic radical having 5 to 10 carbonatoms, or R⁸ and R⁹ are joined together to form an alkyl substituted ornon-substituted ring structure containing 4 to 7 carbon atoms and up to2 atoms selected from nitrogen and oxygen, or R⁸ or R⁹ forms an alkylenegroup of 2 to 4 carbon atoms joining two members of the general formula,the members being the same or different; or,

an acid salt or metal complex of said general formula compound.

A more preferred group of the new compounds are those where: R², R³, R⁴and R⁵ can be hydrogen or methyl,

R can be:

(a) hydrogen or methyl, provided R¹ is not hydrogen, alkyl, --COOH, or--COOC₂ H₅

(b) a cyano group

(c) a nitro group

(d) --R¹⁰ COXR⁶ wherein R¹⁰ is a single covalent bond or methylene, X isdivalent sulfur or oxygen and R⁶ can be:

(i) hydrogen

(ii) a metal salt selected from the group consisting of sodium,potassium and zinc, or a primary or secondary alkylammonium oralkanolammonium moiety

(iii) an alkyl, alkenyl or alkynyl group containing up to 5 carbon atoms

(iv) a cycloalkyl group having 5 to 6 carbon atoms

(v) phenyl

(vi) an hydroxyalkyl, alkoxyalkyl, or alkylaminoalkyl group containingup to 4 carbon atoms

(e) --R¹⁰ COR⁷ wherein R¹⁰ has the meaning specified in (d) and whereinR⁷ can be:

(i) hydrogen

(ii) methyl

(iii) --NR⁸ R⁹ wherein R⁸ and R⁹ can be the same or different and can behydrogen, an alkyl, alkenyl, alkynyl, hydroxyalkyl or alkoxyalkyl havingup to 4 carbon atoms, an aminoalkyl or alkylaminoalkyl having no morethan 5 carbon atoms wherein the sum of the carbon atoms of R⁸ and R⁹ isno greater than 6, a cycloalkyl having 5 to 6 carbon atoms, phenyl, orR⁸ and R⁹ are joined together to form an alkyl substituted ornon-substituted ring structure containing 4 to 6 carbon atoms and up to2 atoms selected from nitrogen and oxygen

R¹ can be:

(a) hydrogen, provided R is not hydrogen or alkyl

(b) alkyl having from 1 to 3 carbon atoms, provided R is not hydrogen,

(c) --CH₂ COXR⁶ wherein X is divalent sulfur or oxygen, and R⁶ can behydrogen, an alkyl having 1 to 2 carbon atoms

(d) CH₂ CONH₂ ; or,

an acid salt or metal complex of said general formula compound.

The most preferred group of the new compounds are those where: R², R³,R⁴ and R⁵ are hydrogen, R, when R¹ is methyl, can be methyl, ethyl, acyano group, a nitro group or --COXR⁶ wherein X is divalent sulfur oroxygen and wherein R⁶ can be: an alkyl, alkenyl, alkynyl oralkylaminoalkyl group having up to 4 carbon atoms, cyclohexyl or phenyl,or

R is --CONR⁸ R⁹ or --CH₂ CONR⁸ R⁹ wherein R⁸ and R⁹ can be the same ordifferent and can be hydrogen or an alkyl group having 1 to 3 carbonatoms, or when either R⁸ or R⁹ is hydrogen, the other group can be anhydroxyalkyl radical having up to 2 carbon atoms, an alkoxyalkyl havingup to 4 carbon atoms, alkylaminoalkyl radical having up to 5 carbonatoms or cyclohexyl, or R⁸ and R⁹ can be joined together to form a ringstructure having 4 to 5 carbon atoms and which can contain an oxygenatom

R¹, can be methyl provided R is methyl, and can be --CH₂ COOCH₃, --CH₂COOC₂ H₅, --CH₂ CONH₂ provided R is hydrogen; or, a salt complex formedby the association of said general formula compound with an acidselected from the group HCl, HBr, HI and H₂ SO₄.

Examples of these new compounds are:

4-methyl-2-(3-pyridyl)5-thiazolecarboxamide

N,4-dimethyl-2-(3-pyridyl)-5-thiazolecarboxamide

N-ethyl-4-methyl-2-(3-pyridyl)-5-thiazolecarboxamide

N-isopropyl-4-methyl-2-(3-pyridyl)-5-thiazolecarboxamide

N-isobutyl-4-methyl-2-(3-pyridyl)-5-thiazolecarboxamide

N-tert-butyl-4-methyl-2-(3-pyridyl)-5-thiazolecarboxamide

N-(2-hydroxyethyl)-4-methyl-2-(3-pyridyl)-5-thiazolecarboxamide

N-(3-dimethylaminopropyl)-2-(3-pyridyl)-4-methyl-5-thiazolecarboxamide

N,N-4-trimethyl-2-(3-pyridyl)-5-thiazolecarboxamide

N,N-diethyl-4-methyl-2-(3-pyridyl)-5-thiazolecarboxamide, and itssulfuric acid salt

N,N-diisopropyl-4-methyl-2-(3-pyridyl)-5-thiazolecarboxamide

4-[4-methyl-2-(3-pyridyl)-5-thiazolylcarbonyl]morpholine

N-dodecyl-4-methyl-2-(3-pyridyl)-5-thiazolecarboxylate and itshydrochloric acid salt

2-(3-pyridyl)-4-thiazolecarboxamide

N-methyl-2-(3-pyridyl)-4-thaizolecarboxamide

4-[2-(3-pyridyl)-4-thiazolylcarbonyl]morpholine

4-methyl-5-nitro-2-(3-pyridyl)thiazole, and its hydrochloric acid salt.

The new compounds of this invention can be made by prior art processes,most conveniently by reacting the appropriate thioamide (II), such asthionicotinamide or a derivative of thionicotinamide, with an alphahalocarbonyl compound (III, where X' is chlorine or bromine). Theresulting 2-(3-pyridyl)thiazole hydrohalide salt (IV) may be isolated assuch or can be converted to the base (V). The synthesis can berepresented by the following equation: ##STR2##

The synthesis can be performed by mixing the thionicotinamide, oralkyl-substituted thionicotinamide with an equivalent quantity of thehalocarbonyl compound in a suitable polar solvent, such as methanol,ethanol, isopropyl alcohol, 2-methoxyethanol or dimethylformamide, andheating the mixture to about 60° to 100° C. for several hours (usuallyfrom two to ten hours). In general, yields are improved by slowly addingto the reactants an approximately equivalent amount, or slightly(preferably two-thirds to one equivalent) less of a tertiary amine suchas triethylamine or other suitable organic base such as pyridine, duringthe course of the reaction. A weak inorganic base such as sodiumbicarbonate can also be used.

The addition of the base probably assists the reaction by neutralizinghydrogen halide which otherwise would form a salt with thethionicotinamide and impede its reaction with the halocarbonyl compound.Without addition of base, reaction of equimolar quantities ofthionicotinamide and ethyl 2-chloroacetoacetate, for example, givesethyl 4-methyl-2-(3-pyridyl)-5-thiazolecarboxylate in yields of only35-40% whereas when an equivalent amount of triethylamine is added,yields of 70-75% are obtained.

Alternatively, the halocarbonyl compound may be reacted withapproximately two equivalents of thionicotinamide or thionicotinamidederivative and the unused thioamide recovered from its hydrogen halidesalt. Thus, the synthesis, as usually performed in making the chemicalsof this invention, can be represented as follows: ##STR3## where B isexcess thioamide or another organic base such as pyridine ortriethylamine. (When sodium bicarbonate is used, carbon dioxide, waterand sodium chloride are formed instead of Base .HX.) Yields can also beimproved by removing the water formed as the reaction proceeds. Thewater can be conveniently removed by azeotropic distillation atatmospheric pressure or under reduced pressure, depending on the solventor solvents used and the reaction temperature required. Solvents such asbutanol, 4-methyl-2-pentanol, 2-methoxyethanol or mixtures of solventssuch as butanol and benzene or toluene are suitable reaction media underthese conditions. For example,N,N,4-trimethyl-2-(3-pyridyl)-5-thiazolecarboxamide is obtained inyields of 60-65% when 2 -chloro-N,N-dimethylacetoacetamide is reactedwith two equivalents of thionicotinamide in 1-butanol at 75° C. withoutwater removel. However, if the water formed is removed by azeotropicdistillation during the reaction, yields are improved to 70-75%.

Some of the chemicals prepared by the above methods, in particular inthe lower alkyl esters of the carboxyl and carboxymethyl derivatives,such as ethyl 4-methyl-2-(3-pyridyl)-5-thiazolecarboxylate, methyl2-(3-pyridyl)-5-thiazolecarboxylate or methyl2-(3-pyridyl)-4-thiazoleacetate, may be employed as intermediates inmaking other chemicals of the invention. For example, ethyl4-methyl-2-(3-pyridyl)-5-thiazolecarboxylate is readily hydrolyzed byheating with aqueous alkali (e.g., sodium hydroxide), and subsequentneutralization of the hydrolysis mixture with acid (e.g., hydrochloricacid or acetic acid) precipitates4-methyl-2-(3-pyridyl)-5-thiazolecarboxylic acid.

Treatment of this acid with thionyl chloride in a suitable solvent, suchas chloroform or toluene, yields4-methyl-2-(3-pyridyl)-5-thiazolecarbonyl chloride hydrochloride whichcan be reacted with ammonia, or a primary or secondary amine, to obtainthe corresponding amides. The acid chloride hydrochlorides can also beused as intermediates for making other derivatives, such as esters, andthioesters.

The following examples illustrate preparation of the compounds of theinvention, and their effective, often selective, attack upon insects.

EXAMPLE I Preparation of Ethyl4-Methyl-2-(3-Pyridyl)-5-Thiazolecarboxylate

Thionicotinamide (207 g., 1.50 moles), isopropyl alcohol (600 ml.) andethyl 2-chloroacetoacetate (250 g., 1.52 moles) were placed in a flaskequipped with a condenser and heated with stirring to 85°-90° C. Aboutone-half hour later, slow dropwise addition of triethylamine (158 g.,1.56 moles) was begun. The addition was made during a period of sixhours, and no solid remained in the reaction mixture after aboutthree-quarters of the amine had been added. The solution subsequentlydarkened considerably. Heating was continued for one hour after all thetriethylamine had been added. When the reaction mixture was cooled, acrystalline precipitate formed, and was removed by filtration. Thecrystals (174 g.) were mainly triethylamine hydrochloride. The filtratewas evaporated under reduced pressure, and water (500 ml.) and toluene(750 ml.) added to the residue. After a small amount of insolublematerial (mostly thionicotinamide) had been removed by filtration, thetoluene and water layers were separated.

The toluene layer was washed three times with ice-cold aqueous 5% sodiumhydroxide (total volume: 600 ml.), and once with water (200 ml.), andwas then extracted three times with dilute hydrochloric acid (totalvolume: 1200 ml., prepared by diluting 200 ml. of concentrated, i.e.,37%, acid). When the combined acid extracts were cooled in ice and madebasic with aqueous ammonia, an oily precipitate was obtained whichsolidified within a few minutes. The solid was broken up, filtered off,washed with water and dried. The light tan product (267 g., 72% yield)melted at 55°-58° C.

Petroleum ether or aqueous ethanol are suitable solvents forrecrystallization. An analytical sample, melting point (m.p.) 57°-60°C., recrystallized from ethanol-water, was found to contain 57.95%carbon, 4.86% hydrogen and 11.06% nitrogen. The values calculated forC₁₂ H₁₂ N₂ O₂ S are 58.04%, 4.87%, and 11.28%, respectively. The meltingpoint of the chemical varied slightly from batch to batch, but ingeneral melting occurred over a range of three to five degrees between55° and 62° C. (because the product exists in two crystalline forms, onemelting at about 58°, and the other, at 62° C.)

EXAMPLE II Preparation of 4-Methyl-2-(3-Pyridyl)-5-ThiazolecarboxylicAcid

A solution of sodium hydroxide (22 g. 0.55 mole) in water (300 ml.) wasmixed with a solution of ethyl4-methyl-2-(3-pyridyl)-5-thiazolecarboxylate (124 g., 0.50 mole) in 95%ethanol (150 ml.). The mixture was heated and stirred for about tenminutes on a steam bath, and then allowed to stand for one hour withoutfurther heating. When the ice-cooled reaction mixture was neutralizedwith dilute hydrochloric acid and acidified with acetic acid, a thickprecipitate of finely divided white solid was obtained. The solid wascollected by filtration, washed thoroughly with water, and dried in anoven at 110° C. The product (106 g., 96% yield) melted withdecomposition at 249°-250° C.

EXAMPLE III Preparation ofN,N-Diethyl-4-Methyl-2-(3-Pyridyl)-5-Thiazolecarboxamide and its Sulfate

A solution of thionyl chloride (40 g., 0.34 mole) in toluene (50 ml.)was added dropwise over a time period of one-half hour to a stirredsuspension of powdered 4-methyl-2-(3-pyridyl)-5-thiazolecarboxylic acid(44 g., 0.20 mole) in toluene (450 ml.) at 50° C. The stirred reactionmixture, which became quite viscous during the addition, was maintainedat 50°-60° C. for another three hours. The heat was removed and a streamof dry air was bubbled slowly through the mixture for about one hourwhile it cooled.

The mixture as cooled further in an ice bath and then filtered to removethe solid, crude 4-methyl-2-(3-pyridyl)-5-thiazolecarboxylic acidchloride hydrochloride, which was washed with fresh toluene (100 ml.)and partially air-dried. The solid was transferred in portions overone-half hour to a stirred, ice-cooled solution of diethylamine (60 g.)in toluene (400 ml.). After the addition was completed the ice-bath wasremoved, and the reaction mixture left overnight at room temperature.The toluene solution was then washed three times with water (50 ml. eachtime), dried over anhydrous sodium sulfate, filtered and evaporatedunder reduced pressure on a steam bath.

Elemental analysis and the nuclear magnetic resonance spectrum of theresidual viscous amber liquid (49 g., 89% yield) confirmed that, apartfrom a remaining trace of toluene, the product was almost pureN,N-diethyl-4-methyl-2-(3-pyridyl)-5-thiazolecarboxamide. After storagein a freezer for several weeks at -15° C., the product crystallized,m.p. 39°-41° C.

Treatment of a cold solution of the amide (14 g.) in ethyl acetate (75ml.) with a cold solution of sulfuric acid (5 g.) in absolute ethanol(20 ml.) gave an immediate precipitate (15.2 g.) of the sulfate salt,m.p. 148°-150° C. Analytical results (C, 45.00%; H, 5.03%) were inagreement with the formula C₁₄ H₁₉ N₃ O₅ S₂, indicating combination ofamide and sulfuric acid.

EXAMPLE IV Preparation ofN,N.4-Trimethyl-2-(3-Pyridyl)-5-Thiazolecarboxamide

Crude 2-chloro-N,N-dimethylacetoacetamide (40 g., about 10% of which was2,2-dichloro-N,N-dimethylacetoacetamide), prepared by reactingN,N-dimethylacetoacetamide with sulfuryl chloride in toluene atapproximately 0° C., was mixed with thionicotinamide (55.2 g., 0.4 mole)and 1-butanol (250 ml.) in a reaction flask equipped with a stirrer,thermometer, Dean-Stark trap and condenser. The mixture was heated withstirring and the pressure in the apparatus lowered until boiling tookplace at 75° C. and the butanol-water azeotrope slowly distilled intothe Dean-Stark trap. A total of 11 ml. of distillate, the aqueous layerof which was slightly over 3 ml., was collected during the next fourhours. The rest of the butanol was then evaporated under vacuum at amaximum temperature of 80° C. The residue was treated with toluene (350ml.) and the undissolved solid (A) collected by filtration. The filtratewas washed three times with a total of 100 ml. of 15% aqueous sodiumhyroxide solution and extracted with dilute hydrochloric acid (30 ml. of37% acid diluted to 120 ml.). The acid extract was made basic withaqueous ammonia and extracted with 150, 50 and 50 ml. portions ofchloroform. The combined chloroform extracts were dried with anhydroussodium sulfate, filtered and evaporated. The viscous amber liquidresidue crystallized on cooling. Yield ofN,N,4-trimethyl-2-(3-pyridyl)-5-thiazolecarboxamide: 38.3 g. m.p.62°-67° C. Recrystallization from ethyl acetate-hexane ortoluene-ligroin raised the melting point to 67°-68° C.

Most of solid A (36.5 g.) dissolved when treated with 300 ml. of waterand 5 ml. of concentrated hydrochloric acid. Basification of thefiltered solution with aqueous ammonia precipitated thionicotinamide(25.7 g., m.p. 183°-185° C. decomp.). The yield ofN,N,4-trimethyl-2-(3-pyridyl)-5-thiazolecarboxamide based onthionicotinamide consumed in the reaction, was 72.5%. When the reactionwas carried out at the same temperature without removal of water byazeotropic distillation the yield was decreased by about 10%.Recrystallization from toluene or toluene-ligroin also yielded anothercrystalline form of the product which melted at 93°-95° C. On storage,the lower melting form changed slowly to the higher melting form.

EXAMPLE V Preparation of 4-Methyl-5-Nitro-2-(3-Pyridyl)Thiazole (or3-(4-Methyl-5-Nitro-2-Thiazolyl)Pyridine) and its Hydrochloride

3-(4-Methyl-2-thiazolyl)pyridine hydrochloride (21.3 g.), prepared bythe procedure of Karrer and Schukri [Helv. Chim. Acta 28, 820 (1945);Chem. Abstr. 40, 1502 (1946)], was added in portions to a cold mixtureof concentrated sulfuric acid (50 ml.) and fuming nitric acid (40 ml.).The reaction mixture was warmed to 60°-65° C. for three hours and thenheated on a steam bath for eight hours. The mixture was cooled, pouredonto ice (300 g.), neutralized with cold 10% sodium hydroxide, and theproduct extracted with chloroform. Evaporation of the chloroformsolution gave 17.5 g. (79% yield) of crude4-methyl-5-nitro-2-(3-pyridyl)thiazole, m.p. 106°-113° C. Afterrecrystallization from ethanol the product melted at 113°-115° C.

Treatment of a filtered solution of the crude product (10 g.) in acetonewith cold concentrated hydrochloric acid (4.5 ml.) gave an immediateprecipitate (10.5 g., 90% yield) of the hydrochloride, m.p. product197°-198° C. decomp. (dependent on rate of heating). Calculated from C₉H₈ ClN₃ O₂ S: C, 41.94%; H, 3.13%. Found: C, 42.23% H, 3.13%.

The following Table B summarizes the preparation of the compounddescribed therein. The preparation methods denoted by the letters Athrough F are:

A. Made directly by reaction of the appropriate thioamide andhalocarbonyl compounds.

B. Made by alkaline hydrolysis of the corresponding methyl or ethylester.

C. Made from the corresponding pyridylthiazolecarboxylic orpyridylthiazoleacetic acid by way of the acid chloride hydrochloride.

D. Made by dehydration of the amide (see compound 17) with phosphoruspentoxide.

E. Made by nitration of the appropriate 3-(4-ethyl-2-thiazolyl)pyridineor its hydrochloride (Example V).

F. Made by ammonolysia of the corresponding methyl or ethyl ester.

The percent yields listed in Table B are based on the starting materialsfor the method indicated. For example, in the cases where method C isindicated, the yields given are for conversion of the appropriatepyridylthiazolecarboxylic or pyridylthiazoleacetic acid to the productsnamed. The figures given do not represent optimum yields, and in manycases higher yields are possible.

                                      TABLE B                                     __________________________________________________________________________                                            Me-                                   Com-                                    thod of                               pound                                   Prepa-                                                                            yield                                                                            M.P. Salts                                                                              M.P. of              No.    Name        R            R.sup.1 ration                                                                            %  (°C.)                                                                       Prepared                                                                           Salt(°C.)     __________________________________________________________________________    1  Methyl 4-methyl-2-(3-pyridyl)-                   Hydro-                       5-thiazolecarboxylate                                                                         COOCH.sub.3  CH.sub.3                                                                              A   71 105-107                                                                            Hydro-                                                                             ca212d               2  Ethyl 4-methyl-2-(3-pyridyl)-                    Hydro-                       5-thiazolecarboxylate                                                                         COOC.sub.2 H.sub.5                                                                         CH.sub.3                                                                              A   72 56-58                                                                              chloride                                                                           206-208d                                                            60-62                                                                              Sulfate                                                                            205-208d             3  4-Methyl-2-(3-pyridyl)-5-                        Potas-                       thiazolecarboxylic acid                                                                       COOH         CH.sub.3                                                                              B   96 249-250d                                                                           sium ca335d               4  Propyl 4-methyl-2-(3-pyridyl)-                                                5-thiazolecarboxylate                                                                         COO(CH.sub.2).sub.2 CH.sub.3                                                               CH.sub.3                                                                              A   14 60-61                          5  Isopropyl 4-methyl-2-(3-                                                      pyridyl)-5-thiazolecarboxyl-                     Hydro-                       ate             COOCH(CH.sub.3).sub.2                                                                      CH.sub.3                                                                              A   19 89-92                                                                              chloride                                                                           205.5-207d                                                               Sulfate                                                                            181-183              6  Pentyl 4-methyl-2-(3-pyridyl)-                                                5-thiazolecarboxylate                                                                         COO(CH.sub.2).sub.4 CH.sub.3                                                               CH.sub.3                                                                              A   64 35-36                          7  Dodecyl                                          Hydro-                       5-thiazolecarboxylate                                                                         COO(CH.sub.2).sub.11 CH.sub.3                                                              CH.sub.3                                                                              A   5  39-42                                                                              chloride                                                                           ca150                8  Cyclohexyl 4-methyl-2-(3-                                                     pyridyl)-5-thiazolecarboxylate                                                                COOC.sub.6 H.sub.11                                                                        CH.sub.3                                                                              A   15 63-64                          9  Allyl 4-methyl 2-(3-pyridyl)-                                                 5-thiazolecarboxylate                                                                         COOCH.sub.2 CHCH.sub.2                                                                     CH.sub.3                                                                              C   29 83-85                          10 Propargy 4-methyl-2-(3-                                                       pyridyl)-5-thiazolecarboxylate                                                                COOCH.sub.2 CCH                                                                            CH.sub.3                                                                              C   29 124-125                        11 Benzyl 4-methyl-2-(3-pyridyl)-                                                5-thiazolecarboxylate                                                                         COOCH.sub.2 C.sub.6 H.sub.5                                                                CH.sub.3                                                                              A   20 83-85                          12 Phenyl 4-methyl-2-(3-pyridyl)-                                                5-thiazolecarboxylate                                                                         COOC.sub.6 H.sub.5                                                                         CH.sub.3                                                                              C   34 72-74                          13 Methoxyethyl 4-methyl-2-(3-                                                   pyridyl)-5-thiazolecarboxylate                                                                COOCH.sub.2 CH.sub.2 OCH.sub.3                                                             CH.sub.3                                                                              A   70 76-78                          14 Dimethylaminoethyl 4-methyl-2-                                                (3-pyridyl)-5-thiazolecarboxyl-                                               ate             COOCH.sub.2 CH.sub.2 N(CH.sub.3).sub.2                                                     CH.sub.3                                                                              C   52 50-53                          15 Phenyl 4-methyl-2-(3-pyridyl)-                                                5-thiazolecarbothiolate                                                                       COSC.sub.6 H.sub.5                                                                         CH.sub.3                                                                              C   55 102-104                        16 4-Methyl-2-(3-pyridyl)-5-                        Hydro-                       thiazolecarboxamide                                                                           CONH.sub.2   CH.sub.3                                                                              C,F 77 204-207                                                                            chloride                                                                           241-242d             17 4-Methyl-2-(3-pyridyl)-5-                                                     cyanothiazole   CN           CH.sub.3                                                                              D   40 98-100                         18 N,4-Dimethyl-2-(3-pyridyl)-                                                   5-thiazolecarboxamide                                                                         CONHCH.sub.3 CH.sub.3                                                                              C   49 148-150                                                                       160-162                        19 N-Ethyl-4-methyl-2-(3-pyridyl)-                                               5-thiazolecarboxamide                                                                         CONHC.sub.2 H.sub.5                                                                        CH.sub.3                                                                              C   63 116-118                        20 4-Methyl-N-propyl-2-(3-pyridyl)-                                              5-thiaxolecarboxamide                                                                         CONH(CH.sub.2).sub.2 CH.sub.3                                                              CH.sub.3                                                                              C   52 109-110                        21 N-Isopropyl-4-methyl-2-(3-                                                    pyridyl)-5-thiazolecarboxamide                                                                CONHCH(CH.sub.3).sub.2                                                                     CH.sub.3                                                                              C   37 143-144                        22 N-Butyl-4-methyl-2-(3-pyridyl)-                                               5-thiazolecarboxamide                                                                         CONH(CH.sub.2).sub.3 CH.sub.3                                                              CH.sub.3                                                                              C   43 95-97                          23 N-tert-Butyl-4-methyl-2-(3-                                                   pyridyl)-5-thiazolecarboxamide                                                                CONHC(CH.sub.3).sub.3                                                                      CH.sub.3                                                                              C   25 103-105                                                                       and                                                                           121-123                        24 N-Hexyl-4-methyl-2-(3-pyridyl)-                  Hydro-                       5-thiazolecarboxamide                                                                         CONH(CH.sub.2).sub.5 CH.sub.3                                                              CH.sub.3                                                                              C   74 103-106                                                                            chloride                                                                           199-203d             25 4-Methyl-N-octyl-2-(3-pyridyl)-                                               5-thiazolecarboxamide                                                                         CONH(CH.sub.2).sub.7 CH.sub.3                                                              CH.sub.3                                                                              C      90-92                          26 4-Methyl-N-tert-octyl-2-(3-                                                   pyridyl)-5-thiazolecarboxamide                                                                CONHC(CH.sub.3).sub.2 CH.sub.2 C                                              (CH.sub.3).sub.3                                                                           CH.sub.3                                                                              C      85-87                          27 N-Cyclohexyl-4-methyl-2-(3-                                                   pyridyl)-5-thiazolecarboxamide                                                                CONHC.sub.6 H.sub.11                                                                       CH.sub. 3                                                                             C   69 63-64                          28 N-Benzyl-4-methyl-2-(3-pyridyl)-                                              5-thiazolecarboxamide                                                                         CONHCH.sub.2 C.sub.6 H.sub.5                                                               CH.sub.3                                                                              C   45 128-129                        29 4-Methyl-2-(3-pyridyl)-5-                                                     thiazolecarboxamide                                                                           CONHC.sub.6 H.sub.5                                                                        CH.sub.3                                                                              A   66 149-152                        30 N,N,4-Trimethyl-2-(3-pyridyl)-                                                5-thiazolecarboxamide                                                                         CON(CH.sub.3).sub.2                                                                        CH.sub.3                                                                              A,C 72,70                                                                            67-68;                                                                        93-95                          31 N,N-Diethyl-4-methyl-2-(3-                                                    pyridyl)-5-thiazolecarboxamide                                                                CON(C.sub.2 H.sub.5).sub.2                                                                 CH.sub.3                                                                              A,C 57,89                                                                            39-41                                                                              sulfate                                                                            148-150              32 N,N-Diisopropyl-4-methyl-2-(3-                                                pyridyl)-5-thiazolecarboxamide                                                                CON[CH(CH.sub.3).sub.2 ].sub.2                                                             CH.sub.3                                                                              C   61 69-70                          33 N,N-Diisobutyl-4-methyl-2-(3-                                                 pyridyl)-5-thiazolecarboxamide                                                                CON[CH.sub.2 CH                                                               (CH.sub.3).sub.2 ].sub.2                                                                   CH.sub.3                                                                              C   23 71-72                          34 1-[4-Methyl-2-(3-pyridyl)-5- thiazolecarbonyl] pyrrolidine                                     ##STR4##    CH.sub.3                                                                              C   66 75-77                          35 1-[4-Methyl-2-(3-pyridyl)-5- thiazolecarbonyl] piperidine                                      ##STR5##    CH.sub.3                                                                              C   54 69-70                          36 4-[4-Methyl-2-(3-pyridyl)-5- thiazolecarbonyl] morpholine                                      ##STR6##    CH.sub.3                                                                              C   69 121-123                        37 N-(2-Hydroxyethyl)-4-methyl-                                                  2-(3-pyridyl)-5-thiazole-                                                     carboxamide     CONHCH.sub.2 CH.sub.2 OH                                                                   CH.sub.3                                                                              C   49 148-150                        38 N-(2-Aminoethyl)-4-methyl-                                                    2-(3-pyridyl)-5-thiazole-                                                     carboxamide     CONHCH.sub.2 CH.sub.2 NH.sub.2                                                             CH.sub.3                                                                              C   27 84-87                          39 N,N'-Ethylenebis-[4-methyl-                                                   2-(3-pyridyl)-5-thiazole-                                                     carboxamide]    CONHCH.sub.2 CH.sub.3                                                                              C   55 287-292d                       40 Ethyl 4-propyl-2-(3-pyridyl)-                                                 5-thiazolecarboxylate                                                                         COOC.sub.2 H.sub.5                                                                         (CH.sub.2).sub.2 CH.sub.3                                                             A   44 66-68                          41 5-Acetyl-4-methyl-2-(3-pyridyl)                  Hydro-                       thiazole        COCH.sub.3   CH.sub.3                                                                              A      78-81                                                                              chloride                  42 2-(3-Pyridyl)-4-thiazole-                                                     carboxamide     H            CONH.sub.2                                                                            C      152-154                        43 N-Methyl-2-(3-pyridyl)-4-                                                     thiazolecarboxamide                                                                           H            CONHCH.sub.3                                                                          C   65 113-115                        44 N,N-Diethyl-2-(3-pyridyl)-                                                    4-thiazolecarboxamide                                                                         H            CON(C.sub.2 H.sub.5).sub.2                                                            C      64-66                          45 4-[2-(3-Pyridyl)-4-thiazole- carbonyl]morpholine                                              H                                                                                           ##STR7##                                                                             C      134-136                        46 Methyl 2-(3-pyridyl)-4-                                                       thiazoleacetate H            CH.sub.2 COOCH.sub.3                                                                  A   21 64-66                          47 Ethyl 2-(3-pyridyl)-4-                           Hydro-                       thiazoleacetate H            CH.sub.2 COOC.sub.2 H.sub.5                                                           A   23 33-34                                                                              chloride                  48 2-(3-Pyridyl)-4-thiazole-                                                     acetic acid     H            CH.sub.2 COOH                                                                         B   86 192-194                        49 Ethyl 4-methyl-2-(5-methyl-                                                   3-pyridyl)-5-thiazole-                                                        carboxylate     COOC.sub.2 H.sub.5                                                                         CH.sub.3                                                                              A   66 77-79                          50 Ethyl 4-methyl-2-(4-methyl-                                                   3-pyridyl)-5-thiazole-                           Hydro-                       carboxylate     COOC.sub.2 H.sub.5                                                                         CH.sub.3                                                                              A   35 60-63                                                                              chloride                                                                           195-197              51 N-Isobutyl-4-methyl-2-(3-                                                     pyridyl)-5-thiazole-                                                          carboxamide     CONHCH.sub.2 CH(CH.sub.3).sub.2                                                            CH.sub.3                                                                              C   62 111-112                        52 N-sec-Butyl-4-methyl-2-(3-                                                    pyridyl)-5-thiazole-                                                          carboxamide     CONHCH(CH.sub.3)CH.sub.2 CH.sub.3                                                          CH.sub.3                                                                              C   66 144-145                        53 4-Methyl-N-(2-pyridyl)-2- (3-pyridyl)-5-thiazole- carboxamide                                  ##STR8##    CH.sub.3                                                                              C   41 184-186                        54 4-Methyl-N-(3-dimethyl-                                                       aminopropyl)-2-(3-pyridyl)-                                                   5-thiazolecarboxamide                                                                         CONH(CH.sub.2).sub.3 N(CH.sub.3).sub.2                                                     CH.sub.3                                                                              C   43 54-56                          55 N,N-Diallyl-4-methyl-2-(3-                       Cal                          pyridyl)-5-thiazolecarboxamide                                                                CON(CH.sub.2 CHCH.sub.2).sub.2                                                             CH.sub.3                                                                              C   61 oil  culated                                                                       for                                                                           C.sub.16 H.sub.17                                                             N.sub.3                                                                       OS:                                                                           C,64.18;                                                                      H,5.72;                                                                       N,14.04                                                                       Found:                                                                        C, 64.17;                                                                     H, 5.65;                                                                      N, 14.11.                 56 N,4-Dimethyl-2-(3-pyridyl)-5-                                                 thiazolecarboxanilide                                                                         CON(CH.sub.3)C.sub.6 H.sub.5                                                               CH.sub.3                                                                              C   42 135-136                        57 N-Ethyl-4-methyl-2-(3-pyridyl)-                                               5-thiazolecarboxanilide                                                                       CON(C.sub.2 H.sub.5)C.sub.6 H.sub.5                                                        CH.sub.3                                                                              C   31 85-86                          58 N-(2-Hydroxyethyl)-N,4-di-                                                    methyl-2-(3-pyridyl)-5-                                                       thiazolecarboxamide                                                                           CON(CH.sub.3)CH.sub.2 CH.sub.2 OH                                                          CH.sub.3                                                                              C   68 83-84                          59 2,6-Dimethyl-4-[4-methyl-2- (3-pyridyl)-5-thiazole- carbonyl]morpholine       5                                                                                              ##STR9##    CH.sub.3                                                                              C   55 Oil  Cal- culated for                                                              C.sub.16 H.sub.19                                                             N.sub.3 O.sub.2 S:                                                            C,60.54; H,6.03;                                                              N,13.24; Found:                                                               C,60.67; H,6.38;                                                              N,13.27                   60 Ethyl 4-methyl-2-(3-pyridyl)                                                  5-thiazolecarbothiolate                                                                       COSC.sub.2 H.sub.5                                                                         CH.sub.3                                                                              C   47 66-67                          61 4-Ethyl-5-methyl-2-(3-pyridyl)-                                               thiazole (or: 3-(4-ethyl-5-                                                   methyl-2-thiazolyl)-pyridine)                                                                 CH.sub.3     C.sub.2 H.sub.5                                                                       A   40 45-47                          62 Methyl-5-methoxycarbonyl-2-                                                   (3-pyridyl)-4-thiazoleacetate                                                                 COOCH.sub.3  CH.sub.2 COOCH.sub.3                                                                  A   34 84-86                          63 N-(3-Methoxypropyl)-4-methyl-                                                 2-(3-pyridyl)-5-thiazole-                                                     carboxamide     CONH(CH.sub.2).sub.3 OCH.sub.3                                                             CH.sub.3                                                                              C   55 85- 86                         64 Diethyl 2-(3-pyridyl)-4,5-                                                    thiazoledicarboxylate                                                                         COOC.sub.2 H.sub.5                                                                         COOC.sub.2 H.sub.5                                                                    A   11 69-71                          65 4,5-Dimethyl-2-(3-pyridyl)                                                    thiazole (or: 3-(4,5-di-                         Hydro-                       methyl-2-thiazolyl)-pyridine)                                                                 CH.sub.3     CH.sub.3                                                                              A   33 63-65                                                                              chloride                                                                           194-196d             66 4-Ethyl-2-(3-pyridyl)thiazole                                                 (or: 3-(4-ethyl-2-thiazolyl)                     Hydro-                       pyridine)       H            C.sub.2 H.sub.5                                                                       A   37 33-35                                                                              chloride                                                                           166-168              67 Ethyl 5-methyl-2-(3-pyridyl)-                                                 4-thiazolecarboxylate                                                                         CH.sub.3     COOC.sub.2 H.sub.5                                                                    A   31 48-51                          68 4-Methyl-5-nitro-2-(3-pyridyl)-                                               thiazole (or: 3-(4-methyl-5-                     Hydro-                       nitro-2-thiazolyl)pyridine)                                                                   NO.sub.2     CH.sub.3                                                                              E   79 113-115                                                                            chloride                                                                           197-198d             *69                                                                              4-Methyl-2-(3-pyridyl)thiazole                                                (or: 3-(4-methyl-2-thiazolyl)                    Hydro-                       pyridine)       H            CH.sub.3                                                                              A   47 46-48                                                                              chloride                                                                           199-201              *70                                                                              Ethyl 2-(3-pyridyl)-4-thiazole-                  Hydro-                       carboxylate     H            COOC.sub.2 H.sub.5                                                                    A      70-72                                                                              bromide                   *71                                                                              2-(3-Pyridyl)-4-thiazole-                                                     carboxylic acid H            COOH    B   91 266-267d                       72 4-Chloro-4-methyl-2-(3-                                                       pyridyl)-5-thiazolecarbox-                                                                    CONHC.sub.6 H.sub.4p-Cl                                                                    CH.sub.3                                                                              A   24 161-163                           anilide                                                                    73 2-(3-pyridyl)-4,5-thiazole-                                                                   CONHC.sub.6 H.sub.4                                                                        CONHC.sub.6 H.sub.4                              dicarboxy-o-toluidide                                                                         o-CH.sub.3   o-CH.sub.3                                                                            C      183-187                        74 4-Ethyl-5-nitro-2-(3-pyridyl)                    Hydro-                       thiazole        NO.sub.2     CH.sub.2 CH.sub.3                                                                     E   60 82-84                                                                              chloride                                                                           173-176d             75 4-Methyl-2-(3-pyridyl)-5- thiazole acetic acid ethyl                                           ##STR10##   CH.sub.3                                                                              A   61 41.5-43.5 57-60                76 4-Methyl-2-(3-pyridyl)-5- thiazole acetic acid.                                                ##STR11##   CH.sub.3                                                                              B   95 183-185                        77 4-Methyl-3-(3-pyridly)-5- thiazoylyl phenyl ketone                                             ##STR12##   CH.sub.3                                                                              A   16 88-89                          78 4-Methyl-2-(3-pyridyl)-5- thiazoleacetamide                                                    ##STR13##   CH.sub.3                                                                              F   57 213-215                        79 N,N,4-Trimethyl-2- (3-pyridyl)-5-thiazoleacetamide                                             ##STR14##   CH.sub.3                                                                              A   17 77-79                          __________________________________________________________________________     In compounds 1 to 48, R.sup.2, R.sup.3, R.sup.4, and R.sup.5 are hydrogen     In compound 49, R.sup.3 is CH.sub.3 ; in compound 50, R.sup.2 is CH.sub.3     Compounds marked with an asterisk are not new.                           

The following examples illustrate the aphicidal use of the compounds ofthe invention.

EXAMPLE VI

The effectiveness of these compounds in controlling aphids wasdemonstrated by applying dilute sprays to barley seedlings infested withCorn Leaf Aphids, Rhopalosiphum maidis, and with the Apple Grain Aphid,Rhopalosiphum prunifoliae.

Compounds tested were prepared for spraying at 2000 ppm (parts permillion) by dissolving the chemical in a small amount of acetone andadding a small amount of a suitable wetting agent. Typically, 0.5 gramof chemical was dissolved in 10 ml. acetone, two drops of Triton X100wetting agent (octylphenoxy polyethoxy ethanol with 9-10 mole percent ofpolyethylene oxide) were added and this was dissolved or suspended in250 milliliters (ml.) of water. Water soluble hydrochloride or sulfatesalts were prepared by the addition of a wetting agent to the chemicalwith the proper amount of water, omitting the acetone solvent.

Barley seedlings, ten per cup, were grown for ten days in 12-ounce cupsof soil. The seedlings were infested with corn leaf and apple grainaphids, and, two days later, the plants were sprayed thoroughly with thecompound to be tested, covering all exposed foliage.

Five days later, results were found by determining the percent controlof aphid populations on treated plants as compared to the population onuntreated plants used as controls. Table C shows the percent control ofaphids obtained at the spray concentration indicated.

                                      TABLE C                                     __________________________________________________________________________    Basic structure:                                                               ##STR15##                                                                    __________________________________________________________________________                                         % Aphid Con-                             Compound                             trol (At p.p.m.                          No.   R                    R.sup.1   Concentration)                                                                        Remarks                          __________________________________________________________________________    1(69) H                    CH.sub.3  99(500)                                  2     H                    CH.sub.3  97(1000)                                                                              HCl salt of (1)                  3     H                    C.sub.2 H.sub.5                                                                         97(500)                                  4     CH.sub.3             CH.sub.3  96(1000)                                 5(65) CH.sub.3             CH.sub.3  93(500) HCl salt of (4)                  6(61) CH.sub.3             C.sub.2 H.sub.5                                                                         60(1000)                                 7(67) CH.sub.3             COOC.sub.2 H.sub.5                                                                      40(1000)                                 8(17) CN                   CH.sub.3  95(1000)                                 9     NO.sub.2             CH.sub.3  88(1000)                                 10(68)                                                                              NO.sub.2             CH.sub.3  86(500) HCl salt of (9)                  11(41)                                                                              COCH.sub.3           CH.sub.3  93(2000)                                 12(3) COOH                 CH.sub.3  93(2000)                                 13    COOH                 CH.sub.3  77(2000)                                 14(1) COOCH.sub.3          CH.sub.3  97(2000)                                 15    COOCH.sub.3          CH.sub.3  93(500) HCl salt of (14)                 16(2) COOC.sub.2 H.sub.5   CH.sub.3  100(1000)                                17    COOC.sub.2 H.sub.5   CH.sub.3  100(2000)                                                                             HCl salt of (16)                 18    COOC.sub.2 H.sub.5   CH.sub.3  93(500) SO.sub.4 salt of (16)            19(4) COOC.sub.3 H.sub.7   CH.sub.3  85(500)                                  20(5) COOi-C.sub.3 H.sub.7 CH.sub.3  100(500)                                 21    COOi-C.sub.3 H.sub.7 CH.sub.3  100(500)                                                                              HCl salt of (20)                 22(6) COOn-C.sub.5 H.sub.11                                                                              CH.sub.3  90(1000)                                 23(7) COOn-C.sub.12 H.sub.25                                                                             CH.sub.3  40(2000)                                 24(9) COOCH.sub.2 CHCH.sub.2                                                                             CH.sub.3  90(500)                                  25(10)                                                                              COOCH.sub.2 CCH      CH.sub.3  100(500)                                 26(8)                                                                                ##STR16##           CH.sub.3  90(500)                                  27(12)                                                                               ##STR17##           CH.sub.3  85(500)                                  28(11)                                                                               ##STR18##           CH.sub.3  80(2000)                                 29(13)                                                                              COO(CH.sub.2).sub.2 OCH.sub.3                                                                      CH.sub.3  96(1000)                                 30(14)                                                                              COO(CH.sub.2).sub.2 N(CH.sub.3).sub.2                                                              CH.sub.3  80(500)                                  31(40)                                                                              COOC.sub.2 H.sub.5   n-C.sub.3 H.sub.7                                                                       80(1000)                                 32(64)                                                                              COOC.sub.2 H.sub.5   COOC.sub.2 H.sub.5                                                                      91(1000)                                 33(60)                                                                              COSC.sub.2 H.sub.5   CH.sub.3  90(1000)                                 34(15)                                                                               ##STR19##           CH.sub.3  80(500)                                  35(16)                                                                              CONH.sub.2           CH.sub.3  100(500)                                 36    CONH.sub.2           CH.sub.3  93(500) HCl salt of (35)                 37(18)                                                                              CONHCH.sub.3         CH.sub.3  100(500)                                 38(22)                                                                              CONHn-C.sub.4 H.sub.9                                                                              CH.sub.3  98(500)                                  39(23)                                                                              CONHtert             CH.sub.3  99(1000)                                       C.sub.4 H.sub.9                                                         40(51)                                                                              CONHi-C.sub.4 H.sub.9                                                                              CH.sub.3  97(500)                                  41(26)                                                                              CONHC(CH.sub.3).sub.2                                                                              CH.sub.3  60(1000)                                       CH.sub.2 C(CH.sub.3).sub.3                                              42(19)                                                                              CONHC.sub.2 H.sub.5  CH.sub.3  100(500)                                 43(20)                                                                              CONH(CH.sub.2).sub.2 CH.sub.3                                                                      CH.sub.3  93(1000)                                 44(21)                                                                              CONHCH(CH.sub.3).sub.2                                                                             CH.sub.3  100(500)                                 45(24)                                                                              CONH(CH.sub.2).sub.5 CH.sub.3                                                                      CH.sub.3  80(2000)                                 46    CONH(CH.sub.2).sub.5 CH.sub.3                                                                      CH.sub.3  97(2000)                                                                              HCl salt of (45)                 47(25)                                                                              CONH(CH.sub.2).sub.7 CH.sub.3                                                                      CH.sub.3  70(1000)                                 48(37)                                                                              CONH(CH.sub.2).sub.2 OH                                                                            CH.sub.3  100(500)                                 49(63)                                                                              CONH(CH.sub.2).sub.3 OCH.sub.3                                                                     CH.sub.3  100(1000)                                50(27)                                                                               ##STR20##           CH.sub.3  86(500)                                  51(29)                                                                               ##STR21##           CH.sub.3  89(1000)                                 52                                                                                   ##STR22##           CH.sub.3  20(2000)                                 53                                                                                   ##STR23##                                                                                          ##STR24##                                                                              30(2000)                                                                              HCl salt                         54(28)                                                                               ##STR25##           CH.sub.3  60(1000)                                 55(53)                                                                               ##STR26##           CH.sub.3  70(1000)                                 56(54)                                                                              CONH(CH.sub.2).sub.3 N(CH.sub.3).sub.2                                                             CH.sub.3  95(500)                                  57(30)                                                                              CON(CH.sub.3).sub.2  CH.sub.3  100(500)                                 58(31)                                                                              CON(C.sub.2 H.sub.5).sub.2                                                                         CH.sub.3  100(500)                                 59    CON(C.sub.2 H.sub.5).sub.2                                                                         CH.sub.3  100(500)                                                                              SO.sub.4 salt of (58)            60(32)                                                                              CON(i-C.sub.3 H.sub.7).sub.2                                                                       CH.sub.3  80(500)                                  61(33)                                                                              CON(i-C.sub.4 H.sub.9).sub.2                                                                       CH.sub.3  45(1000)                                 62(34)                                                                               ##STR27##           CH.sub.3  100(500)                                 63(35)                                                                               ##STR28##           CH.sub.3  85(500)                                  64(36)                                                                               ##STR29##           CH.sub.3  100(500)                                 65(59)                                                                               ##STR30##           CH.sub.3  95(1000)                                 66(55)                                                                              CON(CH.sub.2 CHCH.sub.2).sub.2                                                                     CH.sub.3  90(1000)                                 67(56)                                                                               ##STR31##           CH.sub.3  94(1000)                                 68(57)                                                                               ##STR32##           CH.sub.3  90(1000)                                 69(58)                                                                               ##STR33##           CH.sub. 3 80(1000)                                 70(62)                                                                              COOCH.sub.3          CH.sub.2 COOCH.sub.3                                                                    80(1000)                                 71(71)                                                                              H                    COOH      85(2000)                                 72    H                    COOC.sub.2 H.sub.5                                                                      40(2000)                                 73(70)                                                                              H                    COOC.sub.2 H.sub.5                                                                      60(2000)                                                                              HBr salt of (72)                 74    H                    COOCH.sub.2 CCH                                                                         70(2000)                                 75(48)                                                                              H                    CH.sub.2 COOH                                                                           70(1000)                                 76(47)                                                                              H                    CH.sub.2 COOC.sub.2 H.sub.5                                                             100(500)                                 77    H                    CH.sub.2 COOC.sub.2 H.sub.5                                                             100(1000)                                                                             HCl salt of (76)                 78(46)                                                                              H                    CH.sub.2 COOCH.sub.3                                                                    100(1000)                                79(42)                                                                              H                    CONH.sub.2                                                                              90(500)                                  80(43)                                                                              H                    CONHCH.sub.3                                                                            60(2000)                                 81(44)                                                                              H                    CON(C.sub.2 H.sub.5).sub.2                                                              75(1000)                                 82(45)                                                                              H                                                                                                   ##STR34##                                                                              80(2000)                                 83    H                                                                                                   ##STR35##                                                                              50(2000)                                 84    H                                                                                                   ##STR36##                                                                              60(2000)                                                                              HBR salt of (83)                 85(50)                                                                              COOC.sub.2 H.sub.5   CH.sub.3  95(1000)                                                                              R.sup.2CH.sub.3                  86(49)                                                                              COOC.sub.2 H.sub.5   CH.sub.3  90(500) R.sup.3CH.sub.3                  87                                                                                   ##STR37##                     90(2000)                                 88                                                                                   ##STR38##                     86(500)                                  89(74)                                                                              NO.sub.2             CH.sub.2 CH.sub.3                                                                       20(1000)                                 90(75)                                                                               ##STR39##           CH.sub.3  80(1000)                                 91(76)                                                                               ##STR40##           CH.sub.3  90(1000)                                 92(77)                                                                               ##STR41##           CH.sub.3  50(1000)                                 93(78)                                                                               ##STR42##           CH.sub.3  30(1000)                                 94    NO.sub.2             CH.sub.2 CH.sub.3                                                                       90(1000)                                 95(79)                                                                               ##STR43##           CH.sub.3  98(1000)                                 __________________________________________________________________________     Comparison Data                                                              __________________________________________________________________________    96                                                                                   ##STR44##                     0(2000)                                        (2-pyridyl, not 3-pyridyl)                                              97                                                                                   ##STR45##                     0(2000)                                        (4-pyridyl, not 3-pyridyl)                                              98                                                                                   ##STR46##                     95(500)                                        (nicotine)                                                              __________________________________________________________________________     Numbers in parenthesis beside the compound number are taken from Table B.

EXAMPLE VII

A series of tests were made to show that the compounds of this inventionprotect the parts of a plant above ground when the compounds are appliedto the soil in which the plant had its roots.

Seedling barley plants one to two weeks old were grown in cupscontaining a potting soil mixture. The weight of the soil in each cupwas approximately 400 grams. The chemicals to be tested were dissolvedor suspended in water at concentrations of 600 ppm and of 150 ppm. 26 mlaliquots of each concentration were applied to two pots each, giving afinal dilution in the soil of approximately 40 ppm and 10 ppmrespectively. The barley seedlings were infested with Corn Leaf Aphids,Rhopalosiphum maidis. After six days in the greenhouse, the populationof aphids in the treated pots was compared to that of the untreatedcontrols and the percent control recorded as shown in Table D.

                  TABLE D                                                         ______________________________________                                                         % Control by Soil Drench                                     Chemical           40 PPM     10 PPM                                          ______________________________________                                        4-methyl-2-(3-pyridyl)thiazole                                                                   100        95                                              4-methyl-2-(3-pyridyl)thiazole                                                hydrochloride      100        100                                             4,5-dimethyl-2-(3-pyridyl)                                                    thiazole           100        95                                              4-methyl-2-(3-pyridyl)-5-                                                     thiazolecarboxylic acid                                                                          100        0                                               Ethyl 4-methyl-2-(3-pyridyl)-                                                 5-thiazolecarboxylate                                                                            100        100                                             5-acetyl-4-methyl-2-(3-pyridyl)                                               thiazole           85         40                                              4-methyl-2-(3-pyridyl)-5-                                                     thiazolecarboxamide                                                                              100        90                                              4-methyl-2-(3-pyridyl)-5-                                                     thiazolecarboxanilide                                                                            95         15                                              4-ethyl-2-(3-pyridyl)thiazole                                                                    90         40                                              4-ethyl-2-(3-pyridyl)thiazole                                                 hydrochloride      100        80                                              Nicotine           0          0                                               ______________________________________                                    

In this test, a systemic effect was demonstrated. The plants apparentlyabsorbed the compounds through their roots and transmitted them to theaphid-infested portions where the compounds killed the insects.

EXAMPLE VIII

This example demonstrates the selective effect of one of the preferredcompounds in controlling insects, namely ethyl4-methyl-2-(3-pyridyl)-5-thiazolecarboxylate (A).

The compound was prepared for use by adding 15 grams to 37 milliliters(ml) of super high flash naphtha and 3 ml of Emulfor 719, an emulsifier,and then diluting with water to make up 71/2 liters for a concentrationof 2000 parts per million (ppm) of active ingredient. Similarly,dilutions were made to produce concentrations of 1000 ppm and 500 ppm.

The emulsions were applied as sprays to 10-foot apple trees that hadbeen heavily infested with Green Apple aphids, Aphis pomi. The foliageof the trees was sprayed until thoroughly drenched.

Three days after spraying, leaves on ten shoots per tree were examinedfor aphids, and the number of aphids present was compared to the numberon untreated trees, and to trees sprayed with phosphamidon (B), acommercially available broad spectrum insecticide. Results were:

                  TABLE E                                                         ______________________________________                                                                            Syrphid                                            Rate,   No.      % Control Larvae on                                 Compound ppm     Trees    Aphids    10 shoots*                                ______________________________________                                        A        2000    5        96        1.2                                       A        100     3        88        2.3                                       A        500     4        85        1.25                                      B        300     5        99        0                                         None     --      4        0         0.25                                      ______________________________________                                         *Average after spraying.                                                 

The results showed effective aphid control with both A and B. But Bkilled the beneficial insects (syrphid larvae); its activity was notselective. A selectively killed only harmful insects.

EXAMPLE IX

Many of the compounds of this invention are useful for killingmosquitos.

Compounds were prepared for this use by dissolving 30 milligrams (mg) ofeach in 10 ml of acetone. Dilutions were made with water to the desiredconcentration. Two 25 ml aliquots were placed in test tubes to whichwere added 10 to 25 mosquito larvae. The larvae were fourth instarlarvae of the yellow fever mosquito, Aedes aegypti.

The tubes were held at 70° Fahrenheit (F.) in darkness for 72 hours. Atthe end of this period, the live and dead larvae were counted, and thepercent control was calculated. The results:

                  TABLE F                                                         ______________________________________                                                           % Control                                                                     Mosquito Larvae                                            Compound           (Dosage 10 ppm)                                            ______________________________________                                        4'-Chloro-4-methyl-2-(3-pyridyl)-                                             5-thiazolecarboxanilide                                                                          80                                                         2-(3-pyridyl)-4,5-thiazoledicar-                                              boxy-o-toluidide   90                                                         ______________________________________                                    

What is claimed:
 1. A compound having the general formula ##STR47##wherein R₈ and R₉ are independently selected from the group consistingof (1) hydrogen; (2) alkyl, alkenyl, hydroxyalkyl, alkoxyalkyl,aminoalkyl, alkylaminoalkyl containing up to 8 carbon atoms; (3) C₅ toC₈ cycloalkyl; and (4) C₆ -C₁₀ aryl, haloaryl, aralkyl, alkaryl.
 2. Thecompound of claim 1 wherein R₈ and R₉ are both H.
 3. The compound ofclaim 1 wherein R₈ is H and R₉ is methyl, ethyl, propyl, isopropyl,butyl, isobutyl, sec-butyl, tert-butyl, hexyl, octyl, tert-octyl,cyclohexyl, benzyl, hydroxyethyl, aminoethyl, dimethyl aminopropyl,methoxypropyl, phenyl or p-chlorophenyl.
 4. The compound of claim 1wherein R₈ and R₉ are the same and are methyl, ethyl, isopropyl, allylor isobutyl.
 5. The compound of claim 1 wherein R₈ is methyl and R₉ ishydrooxyethyl.
 6. The compound of claim 1 wherein R₈ is ethyl and R₉ isphenyl.
 7. The compound of claim 1 wherein said compound isN,4-dimethyl-2-(3-pyridyl)-5-thiazolecarboxamide.
 8. The compound ofclaim 1 wherein said compound isN-ethyl-4-methyl-2-(3-pyridyl)-5-thiazolecarboxamide.
 9. The compound ofclaim 1 wherein said compound is N,N,4-trimethyl-2-(3-pyridyl)-5-thiazolecarboxamide.
 10. The compound ofclaim 1 wherein said compound isN,N-diethyl-4-methyl-2-(3-pyridyl)-5-thiazolecarboxamide.